Various publications or patents are referred to in parentheses throughout this application to describe the state of the art to which the invention pertains. Each of these publications or patents is incorporated by reference herein.
The last decade has seen great progress in therapeutic approaches based on vaccination against antigens present on tumor cells and infectious pathogens. Despite the advances made in the identification of new antigens and the elucidation of mechanisms that allow for targeted immune responses against such antigens, a number of challenges remain to be resolved. One obstacle, in particular, is the generation of sufficiently potent immune responses even after the identification of new antigens, as many promising antigenic targets have been shown to be only weakly immunogenic. Because such weak immune responses offer little clinical benefit, the development of effective adjuvants to enhance the immunogenicity of target antigens has become a goal of increasing therapeutic importance.
Immunization strategies to efficiently prime CD8+ T cell responses have come into focus of research activity in current vaccinology. Recent advances in the development of potent adjuvants resulted in two main, alternative approaches, i.e. peptide- and DNA-based vaccine formulation.
In genetic (nucleic acid, RNA or DNA) vaccination, the “vaccine” delivered is a plasmid DNA containing antigen-encoding sequences under control of heterologous promoters that lead to antigen expression in vivo and its immunogenic presentation. The potency to specifically prime TH1-biased immunity makes genetic vaccination an attractive candidate for prophylactic or therapeutic immunization against intracellular pathogens and cancer.
DNA-based vaccines contain unmethylated CpG motifs that stimulate innate host defense mechanisms by triggering the production of TH1-like proinflammatory cytokines, interferones and chemokines (Gurunathan et al., 2000, Annu. Rev. Immunol. 18:927-974). Similarly, synthetic oligonucleotides (ODN) with CpG motifs are potent adjuvants that facilitate priming of a specific TH1 immune responses against a wide variety of pathogens (Krieg, 2002, Annu. Rev. Immunol. 20:709-760). Thus, CpG containing ODN are attractive adjuvants for the formulation of vaccines that exploit the key cell response of the innate or specific immune system. They were shown to be effective in the specific immunotherapy of cancer and allergy in preclinical models. ODN-facilitated priming has been shown to be superior concerning magnitude and longevity of the CD8+ T cell immunity to many alternative adjuvants. In spite of many techniques to deliver ODNs, including injection of “naked”, liposome-entrapped and polymer-absorbed DNA or RNA, the optimal delivery form of ODN as an adjuvant has not been elucidated yet. However, despite their promise as powerful adjuvants, the administration of both polycationic peptides and CpG containing oligonucleotides can exert toxic effects on the host, which limits their usefulness in the clinical context. It would thus be desirable to develop adjuvant systems that provide potent immune stimulation while reducing or eliminating the risk of toxic side effects.